Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.
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We would like to thank Drs. Simon W. Hayward and LaMonica Stewart for cell lines, Lynn M. Matrisian for providing MMP7-Luc plasmid. This work was supported in part by NIH grants MD004038, MD007586, CA091408 and CA163069, UL1 RR024975-01 and UL1 TR000445-06. IF and IHC analysis was performed by Meharry Medical College Morphology Core, which is supported in part by NIH grants U54 MD007593, G12 MD007586, R24 DA036420, and S10RR0254970. We would like to thank Dr. Guoliang Li, Zhanna Alexeyeva, Aigerim Kabulova, Zhibek Keneskhanova, Akerke Altaikyzy for the kind help or assistant on research. Quantum mechanical calculations were performed on the clusters of the Siberian Supercomputer Center (http://www2.sscc.ru) of the Institute of Computational Mathematics and Mathematical Geophysics of the Siberian Branch of the Russian Academy of Sciences.
Conflict of interest
The authors declare that they have no conflict of interest.
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Xie, Y., Fan, H., Lu, W. et al. Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer. Oncogene 38, 2967–2983 (2019). https://doi.org/10.1038/s41388-018-0608-2
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